IDPH-8261--a new nonsteroidal antiinflammatory agent.

IDPH-8261, methyl alpha-methyl-4-(3-thienyl)benzeneacetate, exhibited marked anti-inflammatory activity in acute, subacute and chronic models of inflammation. In rats, IDPH-8261 exhibited a dose related inhibition of carrageenin-induced rat paw edema and the inhibition was greater than ibuprofen, phenylbutazone, but was three times less than indomethacin. It exhibited anti-inflammatory activity in normal and adrenalectomized rats. It also exhibited the activity against various phlogistic agents. IDPH-8261 exhibited AI activity in subacute granuloma tests. In adjuvant-induced established polyarthritis. IDPH-8261 exhibited anti-arthritic effect at a very low dose (ED50 = 4 mg/kg, p.o.). Ulcerogenic liability was the lowest (UD50 = 180 mg/kg, p.o.), when compared to reference standard drugs. Low toxicity and high efficacy may make this compound a potentially useful therapeutic agent.

Involvement of receptors in IDPH-791 induced prolongation of pentobarbitone hypnosis.

IDPH-791, when injected (ip) to mice potentiated the pentobarbitone sleeping time in a dose dependent manner. Involvement of neurotransmitters and receptors in this effect was studied using various receptor blockers, enzyme inhibitors, agonist and an amine depletor. Pretreatment with high dose of yohimbine (0.5 mg/kg), haloperidol, cyproheptadine, atropine and a combination of atropine and yohimbine significantly reversed the activity. Physostigmine, diethyldithiocarbamate and high dose of apomorphine (2.5 mg/kg) potentiated the subminimal effect of IDPH-791, whereas low dose of apomorphine (0.1 mg/kg) failed to potentiate. However, reserpine significantly reversed this response. Prazosin, phenoxybenzamine, low dose of yohimbine (0.25 mg/kg), propranolol, methysergide, mepyramine and cimetidine did not produce any change, thus ruling out the involvement of adrenergic, serotonergic and histaminergic systems. There seems to be simultaneous involvement of muscarinic receptors and postsynaptic dopamine (D2) receptors in IDPH-791 induced potentiation of pentobarbitone hypnosis.

A rapid method for evaluation of analgesic and anti-inflammatory activity in rats.

Carrageenin (2%) was used to produce edema and hyperalgesia; indomethacin, phenylbutazone, aspirin, ibuprofen, analgin, paracetamol and phenacetin were tested at different doses for anti-inflammatory and analgesic activity in the same rats as the peak for the edema reached at the end of 3rd hr and for the hyperalgesia at the end of 4th hr. Indomethacin, phenylbutazone and ibuprofen reduced edema and increased the pain threshold. Analgin and aspirin increased the pain threshold relatively at a low dose. Paracetamol and phenacetin were inactive in the doses tested. Carrageenin (2%) was observed to possess both phlogistic and allogenic properties.

Pre-clinical toxicity of IDPH-791: a new centrally acting muscle relaxant in rats.

IDPH-791, a novel centrally acting muscle relaxant, in doses up to 500 mg/kg (po) for 14 days did not result in any appreciable adverse effect on body weight gain, food or water consumption including biochemical and haematologica parameters in rats. Variations observed in the biochemistry and haematology were either comparable to controls or were within normal limits.

Solvent artifacts likely to be induced by dimethylformamide.

Dimethylformamide (DMF) is widely used as a drug solvent. We found DMF to have wide-spread pharmacological effects including depressant effect on CNS evidenced by a decrease in locomotor activity, body and limb tone and rectal temperature, and potentiation of pentobarbitone sleep. A dose-dependent hypotensive effect was seen in cats and rats. In rats, it was partially blocked by atropine and was associated with bradycardia. DMF antagonised the contractions of smooth muscle induced by many agonists. An atropine sensitive spasmogenic effect was observed on rabbit ileum at 20 ml/l and a direct relaxant effect at 50 ml/l. A positive inotropic effect on guinea pig atria was observed with 5 ml/l. The results indicate DMF concentrations that may not perhaps produce 'solvent artifacts' when used as a solvent.

Involvement of peripheral noradrenaline and 5-hydroxytryptamine in carrageenin-induced pedal oedema in rats.

Role of peripheral and central noradrenaline and 5-hydroxytryptamine in the carrageenin-induced pedal oedema in rats was studied using agents which influence catecholamine synthesis and receptor activity of noradrenaline and 5-hydroxytryptamine. Reserpine, guanethidine, α-methyl-p-tyrosine, diethyldithiocarbamate, 6-hydroxydopamine, phenoxybenzamine, phentolamine, chlorpromazine and yohimbine markedly inhibited carrageenin-induced pedal oedema. However, 6-hydroxydopamine given intracerebroventricularly, 5,6-dihydroxytryptamine, p-chlorophenylalanine, lower dose of yohimbine, pro pranolol, haloperidol, cyproheptadine and mepyramine did not alter the carrageenin-induced oedema, whereas, cyproheptadine and mepyramine given simultaneously, markedly inhibited carrageenin-induced oedema. Our studies indicate that the process of oedema formation in rats by carrageenin involves both the peripheral noradrenaline and 5-hydroxytryptamine.